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J. Biol. Chem., Vol. 279, Issue 48, 49787-49794, November 26, 2004

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The N-terminal Region of the CCAAT Displacement Protein (CDP)/Cux Transcription Factor Functions as an Autoinhibitory Domain that Modulates DNA Binding^*

Mary Truscott¶, Lelia Raynal, Yufa Wang, Ginette Bérubé, Lam Leduy, and Alain Nepveu||**

From the Departments of Biochemistry, ^||Oncology, and ^**Medicine, McGill University, Montreal, Quebec H3A 1A1, Canada

The CCAAT displacement protein/Cut homeobox (CDP/Cux) transcription factor is expressed as multiple isoforms that may contain up to four DNA-binding domains: Cut repeats 1, 2, and 3 (CR1, CR2, CR3) and the Cut homeodomain (HD). The full-length protein, which contains all four DNA-binding domains, is surprisingly less efficient than the shorter isoforms in DNA binding. Using a panel of recombinant proteins expressed in mammalian or bacterial cells, we have identified a domain at the extreme N terminus of the protein that can inhibit DNA binding. This domain was able to inhibit the activity of full-length CDP/Cux and of proteins containing various combinations of DNA-binding domains: CR1CR2, CR3HD, or CR2CR3HD. Since inhibition of DNA binding was also observed with purified proteins obtained from bacteria, we conclude that autoinhibition does not require post-translational modification or interaction with an interacting protein but instead functions through an intramolecular mechanism. Antibodies directed against the N-terminal region were able to partially relieve inhibition. In vivo, the transition between the inactive and active states for DNA binding is likely to be governed by posttranslational modifications and/or interaction with one or more protein partners. In addition, we show that the relief of autoinhibition can be accomplished via the proteolytic processing of CDP/Cux. Altogether, these results reveal a novel mode of regulation that serves to modulate the DNA binding activity of CDP/Cux.

Received for publication, August 18, 2004

^* This research was supported by Grant MOP-11590 from the Canadian Institute of Health Research of Canada (to A. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to these studies.

^¶ The recipient of a studentship from the Terry Fox Foundation.

The recipient of a scholarship from the Fonds de la Recherche en Santé du Québec. To whom correspondence should be addressed: 687 Pine Ave. West, Montreal, Quebec H3A 1A1, Canada. Tel.: 514-934-1934 (ext. 35842); Fax: 514-843-1478; E-mail: alain.nepveu{at}mcgill.ca.

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